The present invention relates to a method for forming a carbonated hydroxyapatite composition and, in particular, to a method for forming carbonated hydroxyapatite compositions which are substantially sodium-free and ammonium-free.
Synthetic hydroxyapatite Ca10(PO4)6(OH)2 has been reported as having been used as a bone replacement material in porous, granular, plasma sprayed and dense forms. Investigations have shown hydroxyapatite to be similar structurally to bone material. However hydroxyapatite is one of the range of stoichiometric calcium phosphate apatites. Human and animal bone mineral have been shown to contain significant amounts of from 3 to 7 wt% of carbonate. There is evidence that the carbonate group can substitute in two sites, the phosphate and hydroxyl sites, termed B and A respectively; bone mineral being predominantly a B type apatite. As a result of this similarity in chemical composition, it is envisaged that carbonated hydroxyapatite will have better bioactivity than unsubstituted stoichiometric hydroxyapatite which is currently used in commercial applications, such as plasma-sprayed coatings on metallic implants and porous hydroxyapatite ceramic bone substitutes. A carbonate substituted hydroxyapatite would also find application for use in chromatography and for purification, such as the removal of heavy metal ions by adsorption.
The preparation of carbonate-substituted hydroxyapatite ceramic materials must be easy and reproducible in order to achieve commercial exploitation. Additionally, the carbonate-substituted hydroxyapatite composition must be thermally stable such that it will not decompose to undesirable secondary phases (e.g. tricalcium phosphate or calcium oxide) upon calcining/sintering. Furthermore, during this heat treatment, the carbonate-substituted hydroxyapatite must not lose the carbonate ions that have been substituted into the hydroxyapatite structure.
Up to the present time, the methods which have been reported to prepare carbonate-substituted hydroxyapatite compositions have involved one of the following procedures.
The heating of a stoichiometric hydroxyapatite ceramic composition in a CO2 atmosphere at approximately 900xc2x0 C. for several days [R. Wallaeys, Silicon, Sulphur, Phosphates. Coll. Int. Union Pure Appl. Chem. Mxc3xcnster (1954) 183-190]. This process results in low levels of carbonate substitution, with poor control over the extent of carbonate substitution and the homogeneity of the substitution throughout the sample. Furthermore, the carbonate substitution is at the wrong site, i.e. the A site, to provide a material which is equivalent to bone.
A wet precipitation method using Na2CO3, NaHCO3 or (NH4)2CO3 as a source of carbonate ions results in the substitution of the additional ions, Na+ or NH4+, into the hydroxyapatite structure, poor thermal stability of the product upon calcining/sintering, the loss of large quantities of the carbonate ions upon heating, and poor control of the levels of the carbonate substitution. See, for example: Y. Doi, Y. Moriwaki, T. Aoba, M. Okazati, J. Takahashi and K. Joshin, xe2x80x9cCarbonate apatites from aqueous and non-aqueous media studied by esr, IR and X-Ray Diffraction: Effect of NH4+ ions on crystallographic parametersxe2x80x9d, J. Deut. Res. 61(1982) 429-434. D. G. A. Nelson and J. D. B. Featherstone, xe2x80x9cPreparation analysis and characterization of Carbonated apatitesxe2x80x9d, Calcif. Tiss. Int. 34(1082) 569-581.
EP-A-0722773 and JP-A-8225312 disclose the preparation of an A-type substituted hydroxyapatite in which the carbonate ions substitute for OHxe2x88x92 ions in the structure.
EP-A-0626590 discloses the preparation of a carbonate substituted apatite in which the Ca/P ratio is maintained at approximately 1.66 and sodium and carbonate ions are co-substituted into the lattice with the amount of carbonate that is substituted being controlled by the amount of sodium bicarbonate used in the reaction.
WO-A-94/08458 discloses a process for the preparation of carbonated hydroxyapatite in which the starting materials are mixed at room temperature and the material sets to form a cement at room or physiological temperature. The source of carbonate ions is solid calcium carbonate. The material produced is poorly-crystalline or amorphous apatite which contains sodium ions.
JP-A-61151011 discloses adding Ca(OH)2 and CaCO3 to a slurry of CaHPO4. The CO3 ions are introduced into the reaction mixture as insoluble CaCO3 and not via solution. The ratios of Ca/P used are always less than 1.67. After sintering at 1000xc2x0 to 1100xc2x0 C. the carbonate content of the resulting material is less than 0.1%.
It is mainly due to the problems encountered with the preparation routes discussed above that these routes have not been developed to prepare carbonate-substituted hydroxyapatite ceramic materials commercially.
We have now developed a novel process for the preparation of a single phase carbonate-substituted hydroxyapatite composition which overcomes the problems of the prior art methods and does not contain sodium or ammonium ions.
Accordingly, the present invention provides a process for the preparation of a carbonate-substituted hydroxyapatite, which process comprises the steps of
(i) preparing an aqueous solution containing CO32xe2x88x92 and PO43xe2x88x92 ions in the substantial absence of cations other than H+ ions:
(ii) mixing the solution from step (i) with an aqueous solution or suspension of a calcium compound; and
(iii) collecting and drying the precipitate formed in step (ii);
the ratio of Ca/P in the calcium-containing solution or suspension and the phosphorus-containing solution, when mixed together, being maintained above 1.67.
The single-phase carbonate-substituted hydroxyapatite compositions prepared in accordance with the present invention are believed to be novel and, accordingly, in another aspect the present invention provides a single phase carbonate-substituted hydroxyapatite composition, with a Ca/P ratio of greater than 1.67, which comprises up to 5% by weight of CO32xe2x88x92 ions substituted in the B (PO4) site or the B and A sites of the hydroxyapatite structure, with at least 50% of the CO32xe2x88x92 ions substituted on the B site, and which does not contain Na+ or NH4+ ions.
In carrying out the process of the present invention the aqueous solution of step (i) may be prepared by bubbling carbon dioxide through water to form carbonic acid, and then adding phosphoric acid, H3PO4, thereto, or by adding carbon dioxide gas to water under high pressure and then adding phosphoric acid thereto. The amount of carbon dioxide absorbed by the solution can be calculated from the pH of the solution prior to the addition of H3PO4. At a pH of about 4.0 the solution will be fully saturated with carbon dioxide. Generally H3PO4 will be added to the solution of carbonic acid in order to provide the PO43xe2x88x92 ions for reaction.
Alternatively, the aqueous solution of step (i) may be prepared by bubbling carbon dioxide through a solution of H3PO4 or adding carbon dioxide under pressure to the solution, in order to form CO32xe2x88x92 ions in situ. Furthermore, CO2 may be introduced as a solid which carbonates the solution as it vaporises.
The solution from step (i) of the process is mixed in step (ii) with an aqueous solution or suspension of a calcium compound. For example, a solution of calcium nitrate, Ca(NO3)2, or a suspension of calcium hydroxide, Ca(OH)2, may be used. Preferably the mixing will be carried out by dropwise addition of the solution from step (i) to the calcium-containing solution or suspension. However, bulk mixing of the solution and the suspension may be undertaken provided that the combined mixture is vigorously stirred in order to provide the precipitation reaction.
During the mixing in step (ii) of the process carbon dioxide may be bubbled through the mixture.
The ratio of Ca to P in the calcium-containing solution or suspension and the phosphorus-containing solution, when mixed together, is maintained at above 1.67 in order to promote substitution in both the A and B sites to give an AB-substituted hydroxyapatite if having the formula:
Ca10(PO4)6xe2x88x92x(CO3)x(OH)2xe2x88x92y(CO3)y
Preferably the Ca/P ratio is maintained in the range from above 1.67 to 1.84, more preferably from above 1.67 to 1.76.
After the addition of the reactants is complete the pH of the mixture may be adjusted, if desired, to pH 10 to 11 by the addition of ammonia. If ammonia is added in this manner then appropriate steps are taken to remove the ammonia from the final product.
The dried precipitate from step (iii) of the process may be calcined/sintered in a wet carbon dioxide atmosphere according to the teaching of EP-0625490B. In particular, the dried precipitate may be calcined in carbon dioxide containing from 0.001 to 0.10 of grams of water per liter of gas at a temperature in the range of from 700xc2x0 to 1200xc2x0 C., preferably from 900xc2x0 to 1200xc2x0 C. Preferably the carbon dioxide used as the sintering atmosphere will contain from 0.01 to 0.02 grams of water per liter of gas. The sintering time will generally be up to 24 hours, preferably 10 minutes to 4 hours.
The sintering will generally be carried out at atmospheric pressure, i.e. no imposed pressure, although pressures slightly higher than atmospheric may be produced by the particular configuration of the furnace used.
The carbonated hydroxyapatite compositions produced according to the process of the present invention will generally comprise up to 5% by weight of CO32xe2x88x92 ions, preferably from 3 to 5% by weight. Furthermore, the carbonated hydroxyapatite composition will generally have from 50 to 85% of the CO32xe2x88x92 ions substituted on the B site.
The carbonated hydroxyapatite compositions produced according to the process of the present invention are prepared in the substantial absence of cations other than H+ and Ca2+. Accordingly, the compositions do not contain other cations, such as Na+ or NH4+, substituted in their structures, and thus are biocompatible. The carbonated hydroxyapatite compositions prepared in accordance with the present invention may be used in any of the applications for which hydroxyapatite is used, for example the formation of plasma-sprayed coatings on metallic implants, the formation of porous ceramic bone substitutes, the preparation of composites with polymeric materials such as high density polyethylene, as granules or beads for packing or filling bone defects, as materials for use in chromatography or as materials for use in purification methods such as the removal of heavy metals by adsorption.